Traditionally and historically, liquid handling constitutes a fundamental building block of most biochemical, chemical and biological tests performed across multiple industries.
Liquid handling is essentially defined as the operations of putting one sample in contact with another one, sometimes in a repetitive way, being able to quantify the amount of at least one of the two samples to be used. Despite the fact that a narrow definition of liquid strictly indicates materials in the liquid form, hereafter we refer to liquid handling the generic operation of handling materials in the solid (for example powders), liquid or gaseous form—or in any mixture of these states (for example, heterogeneous samples containing solid and liquids mixed together like cell cultures and emulsions or gases and liquids mixed together like gels).
In the liquid handling arena, most solutions can be characterized by different degrees of performances, where the performances are defined according different aspects which are of interest to the user, and constitute a reason for utility: for example, flexibility, ease of use, throughput, reproducibility, traceability, and cost-effectiveness. Flexibility is defined as the capability of dealing with heterogeneous processes, over a wide range of volumes and for different characteristics of the liquids, but also in respect to other properties and requirements. Ease of use is defined as the quality of requiring minimal training for its adoption, and a faster and intuitive translation of the user intent into the proper and desired operation. In particular, the translation of the user intent to perform a desired operation—without requiring a direct involvement during its execution—is also referred to as programmability. Throughput is defined as the amount of independent, partially dependent or dependent processes that can be performed within a suitable unit of time. Reproducibility is defined as minimal variations between different implementations of the same protocol for any reason. Reproducibility can be evaluated for protocols performed simultaneously or at a different moments by the same operator or device, but it can also include variations introduced by different operators or different devices—in particular when evaluated with respect to the target performances as defined by the user, also referred to as precision. For example, lack of precision in a biological process can be generated by a slow clock used for the timing of the liquid handling steps—or by an incorrect calibration of the volumetric scale of the liquid handling device. Traceability is defined as the property of keeping record, for a-posteriori analysis and verification, of the actual process that has been implemented, including unpredictable events during the protocol execution like possible faults or mistakes. Cost effectiveness is defined as the weighted sum of the cost components in the acquisition of a liquid handling apparatus, user training, cost of consumables, cost of maintenance, cost of operations, cost of repair and cost of dismissal at the end of its lifetime.
Liquid handling today is performed either manually by human operators, or by means of automatic devices of various types.
In the most conventional laboratory environment, liquid handling is performed by means of tools—defined as pipettes—allowing for a quantitative estimation of the sample being transported. In the case of liquids, a common practice is to estimate the amount of sample by means of its volume. Therefore, manual liquid handling is typically performed by means of volumetric adjustable pipettes capable of transporting liquid from one recipient to another in a known amount pre-defined by an operator. Hereafter we define as pipette the liquid handling tool available and initially foreseen for the procedures of manual liquid handling, or at least partially conceived for this application or simply inspired to the tool used for this purpose. It should also be mentioned that two types of pipettes are commercially available: electronic pipettes and mechanical pipettes. While electronic pipettes present some advantages in terms of calibration and ergonomics, mechanical pipettes still represent a large fraction of the market, being economical, performing, robust, cheaper and simple to operate. Above all, they've become an industry standard tool responding to very precise norms, for example ISO 8655 normatives. The difference in ergonomics is mainly related to the force to be applied by the operator thumb (defined also as thumb action) on the pipette itself, for example for the purpose of liquid aspiration, dispensing, mixing, and tip ejection. The overall set of procedures involving a pipette is hereafter referred to as manipulation of the pipette.
In most cases, for the purpose of avoiding contamination, pipettes are typically interfaced to the sample by means of tips, which are consumables meant to avoid a direct contact of the pipette itself with the liquid—that otherwise will unavoidably transport undesired molecules to undesired places. The use of tips has become a standard practice in industrial and research environments, with multiple types available and chosen by customers according to their maximum volume, presence of filters, surface absorption properties of molecules, materials, brands and ultimately cost. Pipette tips can be considered specific pipette accessories or in alternative as part of a larger class of laboratory devices defined as consumables, that include among others microplates, tubes, Eppendorf tubes, microtubes, vacutainers, filters, containers, capsules, vials and bottles typically used in the field of liquid handling and biological or chemical reactions.
In recent years, the pharmaceutical, biotechnology, chemical, healthcare and related industries have increasingly adopted automated solutions for performing various reactions and analyses. The benefits of these automatic devices include reproducibility, speed, capacity and ultimately cost reductions at high throughput, enabling some users to perform a large number of reactions with limited human intervention, typically performing multiple reactions in parallel.
Automatic devices are usually associated to laboratories which require large production capacity—since their size, cost and complexity of operations induce users adopting them when a significant number of processes to be performed. However, sometimes automatic devices are also used in low and medium throughput environments, when the features of reproducibility and traceability are strictly required—like in the sector of healthcare and diagnostics.
Examples of applications in the sector of healthcare consists in the processing of heterogeneous biofluids, defined as biological or chemical fluids which present different components which are visually selectable at the macroscopic level. A known example consists of processing separated blood, for example following fractionation, with the purpose of separating buffy coat from erythrocytes and plasma (or serum). Extraction of the buffy coat from the tube by manual pipetting is a very unreliable, imprecise, difficult and time consuming operation. Therefore, blood banks employ dedicated automated systems of large complexity, like the one described by Quillan et al. (International Journal of Epidemiology 2008; 37:i51-i55) which are addressing the need of precise and reproducible operations at high throughput. However, also smaller clinical environments, like hospitals and analysis laboratories, dealing with a smaller number of patient samples would profit of the same advantages of reproducibility at a more limited throughput.
Cost of automatic devices is often linked to their mechanical complexity: precise and reproducible movements over a large area require precision mechanics, including undeformable metallic frames determining a significant weight, ultimately making these systems not transportable and expensive to manufacture. Weight and dimensions has also a significant impact on the cost of operations, since maintenance, repairs, training and upgrades have to be performed by specialized personnel on-site. And heavy systems imply stronger motors and higher electrical current absorption, making their design more complex and expensive to produce. Not to speak about portability of the devices and an easy integration into an existing laboratory.
Among others, a crucial requirement of a liquid handling process is its actual reproducibility with respect to state-of-art validated protocols. Since most of the assay development is performed by means of manual liquid handling, it is obvious that results emerging from manual liquid handling often constitute the reference for a given liquid handling system. However, it is well known to those skilled in the art (for example, Pandya et al.—Journal of Pharmaceutical and Biomedical Analysis 53, 2010, pg. 623-630) that manual liquid handling misses in particular traceability, precision and reproducibility. This is partially taken care by tools calibration and performances, since above all it is consequence of the human nature and the propagation of instructions between humans, training included. In addition, the low acquisition cost of manual liquid handling tools should not hide the significant cost of operations generated by the necessity of having human operators. This is particularly true since it also emerged that repetitive operations involving pipettes introduce a significant strain on the musco-skeletal system, with possible consequence of work-related diseases. So, the potential productivity of one operator has to be limited to minimize the risk of occurrence of different pathologies, like cumulative trauma disorders (CTDs) and repetitive strains injuries (RSIs). Obviously, it would be desirable to remove these risks completely from the professional environment—however the straight replacement of humans with automatic liquid handling systems clashes against the need of flexibility, which is required in various activities, but also collides with economic considerations due to the significant initial cost to be undertaken for the adoption and operation of automated infrastructure. In summary, there is the current evidence of a gap between manual liquid handling operations and automatic liquid handling systems—which ultimately address in different ways liquid handling targets but do not overlap in utility. The present inventions address this gap, providing a useful tool to research environments and industry.
Another crucial requirement of a liquid handling system consists in its transportability, and a small space usage in a laboratory. Transportability enables a lower final cost to the user, avoiding on-site installation of the system and on-site support and maintenance. A system with a small footprint and light weight allows its installation in a conventional laboratory environment without the need of specific infrastructure, and better integration into the existing laboratory workflow. A light system additionally absorbs less electrical current, enabling the possibility of battery or solar power in those areas where electrical supply is limited.
As pipettes, including state-of-art design solutions for the purpose of manual liquid handling, a summary of some of the prior art includes:                Gilson et al. (U.S. Pat. No. 3,827,305) teach a hand-help pipette with adjustable volume mechanism;        Magnussen et al. (U.S. Pat. No. 4,905,526) teach an electrically assisted pipette;        Scordato et al. (U.S. Pat. No. 4,821,586) teach an example of computer controlled pipette;        Gilson et al. (U.S. Pat. No. 6,158,292) teach a tip ejection system for a liquid handling pipette;        Cronenberg et al. (U.S. Pat. No. 6,977,062) teach an automatic tip removal system including tip identification methods.        
As automatic liquid handling systems, their engineering solutions and their conceptual design, a summary of some of the prior art is as follows:                Gilman et al. (U.S. 2003/0225477) disclose a modular equipment apparatus and methods for handling labware        Pfost et al. (U.S. Pat. No. 5,104,621) disclose an automated multi-purpose analytical chemistry processing center and laboratory workstation.        Shumate et al. (U.S. Pat. No. 6,372,185) disclose a liquid chemical distribution method and apparatus        Bjornson et al. (U.S. 2006/0127281) disclose a pipetting apparatus with integrated liquid level and/or gas bubble detection.        Kowalski et al. (U.S. Pat. No. 5,139,744) disclose an automated laboratory workstation having module identification means.        As other solutions, integrating automation into dedicated systems at low throughput,or describing dedicated systems to specific applications, the prior art includes:        Zucchelli et al. (U.S. Pat. No. 7,152,616) teach devices and methods for programmable microscale manipulation of fluids;        Blanton et al. (U.S. Pat. No. 7,601,300) teach a compact integrated system for processing test samples at low throughput in a diagnostics environment.        Clark et al. (U.S. Pat. No. 5,482,861) teach an automated continuous and random access analytical system;        Wegrzyn et al. (U.S. 2004/0241872) teach an optical detection liquid handling robot system;        Ruddock et al. (U.S. Pat. No. 7,105,129) teach a liquid handling robot for well plates using a powered anvil.        
One drawback of prior art, in general, has been the difficulty to reconcile flexibility, in the form of fully programmable and configurable devices, with simplicity, in the form of low cost manufacturing and low cost operation, and reproducibility, characteristic of automated liquid handling systems.
The present invention meets the need for a flexible, reproducible, traceable, solution to perform liquid handling, at the same time improving the advantages of manual operations and introducing the benefits of automation at lower cost.